EZH2 mediates both PRC2-dependent gene silencing via catalyzing H3K27me3 and PRC2-independent transcriptional activation in various cancers. Given its oncogenic role in cancers, EZH2 has constituted a compelling target for anticancer therapy. However, current EZH2 inhibitors only target its methyltransferase activity to downregulate H3K27me3 levels and show limited efficacy because of inadequate suppression of the EZH2 oncogenic activity. Therefore, therapeutic strategies to completely block the oncogenic activity of EZH2 are urgently needed. Herein, we report a series of EZH2-targeted proteolysis targeting chimeras (PROTACs) that induce proteasomal degradation of PRC2 components, including EZH2, EED, SUZ12, and RbAp48. Preliminary assessment identified E7 as the most active PROTAC molecule, which decreased PRC2 subunits and H3K27me2/3 levels in various cancer cells. Furthermore, E7 strongly inhibited transcriptional silencing mediated by EZH2 dependent on PRC2 and transcriptional activation mediated by EZH2 independent of PRC2, showing significant antiproliferative activities against cancer cell lines dependent on the enzymatic and nonenzymatic activities of EZH2.

中文翻译：

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基于EZH2的PROTAC的设计和合成，以降解PRC2配合物以靶向EZH2的非催化活性

在各种癌症中，EZH2通过催化H3K27me3和PRC2独立的转录激活介导了PRC2依赖的基因沉默。鉴于其在癌症中的致癌作用，EZH2已成为抗癌治疗的引人注目的靶标。但是，由于对EZH2致癌活性的抑制不充分，目前的EZH2抑制剂仅以其甲基转移酶活性为目标来下调H3K27me3水平并显示出有限的功效。因此，迫切需要完全阻断EZH2致癌活性的治疗策略。本文中，我们报告了一系列针对EZH2的蛋白水解靶向嵌合体（PROTAC），可诱导PRC2组分（包括EZH2，EED，SUZ12和RbAp48）的蛋白酶体降解。初步评估确定为E7作为最活跃的PROTAC分子，可降低各种癌细胞中的PRC2亚基和H3K27me2 / 3水平。此外，E7强烈抑制依赖于PRC2的EZH2介导的转录沉默和独立于PRC2的EZH2介导的转录激活，显示出对癌细胞系的显着抗增殖活性，这取决于EZH2的酶促和非酶促活性。